Miltefosine
Encyclopedia
Miltefosine is a phospholipid
drug
.
Originally developed as an antineoplastic (and licenced for topical use), it is finding use as an antiprotozoal drug. It can be administered orally and topically.
It acts as an Akt
inhibitor.
It is also under investigation as a potential therapy against HIV
infection.
: Miltefosine is registered and used by Zentaris GmbH in India
, Colombia
and Germany
for the treatment of visceral
and cutaneous leishmaniasis
, and is undergoing clinical trial
s for this use in several other countries, such as Brazil
and Guatemala
.
Several medical agents have some efficacy against visceral or cutaneous leishmaniasis, however a 2005 survey concluded that Miltefosine is the only effective oral treatment for both forms of leishmaniasis.
as long-lived HIV-1 reservoirs. The HIV protein Tat activates pro-survival PI3K/Akt
pathway in primary human macrophages. Miltefosine acts by inhibiting the PI3K/Akt pathway
, thus removing the infected macrophages from circulation, without affecting healthy cells.
s reported with miltefosine treatment are nausea
and vomiting
. Miltefosine has exhibited teratogenicity, and should not be administered to pregnant
women.
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
.
Originally developed as an antineoplastic (and licenced for topical use), it is finding use as an antiprotozoal drug. It can be administered orally and topically.
It acts as an Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
inhibitor.
It is also under investigation as a potential therapy against HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection.
Current antiprotozoal and antifungal applications
LeishmaniaLeishmania
Leishmania is a genus of Trypanosomatid protozoa, and is the parasite responsible for the disease leishmaniasis. It is spread through sandflies of the genus Phlebotomus in the Old World, and of the genus Lutzomyia in the New World. Their primary hosts are vertebrates; Leishmania commonly infects...
: Miltefosine is registered and used by Zentaris GmbH in India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
, Colombia
Colombia
Colombia, officially the Republic of Colombia , is a unitary constitutional republic comprising thirty-two departments. The country is located in northwestern South America, bordered to the east by Venezuela and Brazil; to the south by Ecuador and Peru; to the north by the Caribbean Sea; to the...
and Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
for the treatment of visceral
Visceral leishmaniasis
Visceral leishmaniasis , also known as kala-azar, black fever, and Dumdum fever, is the most severe form of leishmaniasis. Leishmaniasis is a disease caused by protozoan parasites of the Leishmania genus. This disease is the second-largest parasitic killer in the world , responsible for an...
and cutaneous leishmaniasis
Cutaneous leishmaniasis
Cutaneous leishmaniasis is the most common form of leishmaniasis. It is a skin infection caused by a single-celled parasite that is transmitted by sandfly bites...
, and is undergoing clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s for this use in several other countries, such as Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
and Guatemala
Guatemala
Guatemala is a country in Central America bordered by Mexico to the north and west, the Pacific Ocean to the southwest, Belize to the northeast, the Caribbean to the east, and Honduras and El Salvador to the southeast...
.
Several medical agents have some efficacy against visceral or cutaneous leishmaniasis, however a 2005 survey concluded that Miltefosine is the only effective oral treatment for both forms of leishmaniasis.
Investigatory antiprotozoal and antifungal usage
Miltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs. Animal and in-vitro studies suggest it may have broad anti-protozoal and anti-fungal properties:- Animal studies suggest miltefosine may also be effective against Trypanosoma cruziTrypanosoma cruziTrypanosoma cruzi is a species of parasitic euglenoid trypanosomes. This species causes the trypanosomiasis diseases in humans and animals in America...
, the parasite responsible for Chagas' disease.
- Several studies have found the drug to be effective against Cryptococcus neoformansCryptococcus neoformansCryptococcus neoformans is an encapsulated yeast that can live in both plants and animals. Its teleomorph is Filobasidiella neoformans, a filamentous fungus belonging to the class Tremellomycetes. It is often found in pigeon excrement....
, CandidaCandida (genus)Candida is a genus of yeasts. Many species are harmless commensals or endosymbionts of animal hosts including humans, but other species, or harmless species in the wrong location, can cause disease. Candida albicans can cause infections in humans and other animals, especially in immunocompromised...
, AspergillusAspergillusAspergillus is a genus consisting of several hundred mold species found in various climates worldwide. Aspergillus was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli...
and FusariumFusariumFusarium is a large genus of filamentous fungi widely distributed in soil and in association with plants. Most species are harmless saprobes, and are relatively abundant members of the soil microbial community. Some species produce mycotoxins in cereal crops that can affect human and animal health...
.
- An in-vitro study found that Miltefosine is effective against metronidazole-resistant variants of Trichomonas vaginalisTrichomonas vaginalisTrichomonas vaginalis is an anaerobic, flagellated protozoan, a form of microorganism. The parasitic microorganism is the causative agent of trichomoniasis, and is the most common pathogenic protozoan infection of humans in industrialized countries. Infection rates between men and women are the...
, a sexually transmitted protozoal disease.
- Hexadecyltrimethylammonium bromideHexadecyltrimethylammonium bromideCetrimonium bromide is one of the components of the topical antiseptic cetrimide. The cetrimonium cation is an effective antiseptic agent against bacteria and fungi.It is a cationic surfactant...
, a compound structurally similar to miltefosine, was recently found to exhibit potent in vitroIn vitroIn vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
activity against Plasmodium falciparumPlasmodium falciparumPlasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
.
Investigatory usage against HIV infection
Miltefosine targets HIV infected macrophages, which play a role in vivoIn vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
as long-lived HIV-1 reservoirs. The HIV protein Tat activates pro-survival PI3K/Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
pathway in primary human macrophages. Miltefosine acts by inhibiting the PI3K/Akt pathway
PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer e.g. breast cancerand non-small-cell lung cancer.]PI3K activation activates AKT which activates mTOR....
, thus removing the infected macrophages from circulation, without affecting healthy cells.
Side effects
The main side effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s reported with miltefosine treatment are nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. Miltefosine has exhibited teratogenicity, and should not be administered to pregnant
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
women.
External links
- Eissa M. M., Bardicy S. E. & Tadros M. (2011). "Bioactivity of miltefosine against aquatic stages of Schistosoma mansoni, Schistosoma haematobium and their snail hosts, supported by scanning electron microscopy". Parasites & VectorsParasites & VectorsParasites & Vectors is a peer-reviewed open-access medical journal published by BioMed Central. The journal publishes articles on the biology of parasites, parasitic diseases, intermediate hosts, vectors and vector-borne pathogens. Parasites & Vectors was established in 2008 as a merger of Filaria...
4: 73. doi:10.1186/1756-3305-4-73.